Thanks for your reply....Yes, it is the only medication I am taking. I am not diabetic though. And it has been months since chemo. I'm just worried and was wondering if other people are suffering from similar symptoms while on the trial/off-label.

Metformin Prevents Tumors From Growing In Human Cultures

An inexpensive drug that treats Type-2diabetes has been shown to prevent a number of natural and man-made chemicals from stimulating the growth of breast cancer cells, according to a newly published study by a Michigan State University researcher.

The research, led by pediatrics professor James Trosko and colleagues from South Korea's Seoul National University, provides biological evidence for previously reported epidemiological surveys that long-term use of the drug metformin for Type-2 diabetes reduces the risk of diabetes-associated cancers, such as breast cancers.

The research appears in the current edition of PLoS One.

"People with Type-2 diabetes are known to be at high risk for several diabetes-associated cancers, such as breast, liver and pancreatic cancers," said Trosko, a professor in the College of Human Medicine's Department of Pediatrics and Human Development. "While metformin has been shown in population studies to reduce the risk of these cancers, there was no evidence of how it worked."

For the study, Trosko and colleagues focused on the concept that cancers originate from adult human stem cells and that there are many natural and man-made chemicals that enhance the growth of breast cancer cells.

Using culture dishes, they grew miniature human breast tumors, or mammospheres, that activated a certain stem cell gene (Oct4A). Then the mammospheres were exposed to natural estrogen - a known growth factor and potential breast tumor promoter - and man-made chemicals that are known to promote tumors or disrupt the endocrine system.

The team found that estrogen and the chemicals caused the mammospheres to increase in numbers and size. However, with metformin added, the numbers and size of the mammospheres were dramatically reduced. While each of the chemicals enhanced growth by different means, metformin seemed to be able to inhibit their stimulated growth in all cases.

"While future studies are needed to understand the exact mechanism by which metformin works to reduce the growth of breast cancers, this study reveals the need to determine if the drug might be used as a preventive drug and for individuals who have no indication of any existing cancers," he said.

"Though we still do not know the exact molecular mechanism by which it works, metformin seems to dramatically affect how estrogen and endocrine-disrupting chemicals cause the pre-existing breast cancers to grow."

I hope we see some talk/study results at the Breast Cancer conference in San Antonio this week about Metformin.

New 'Achilles' Heel' In Breast Cancer: Tumor Cell Mitochondria

Researchers at the Kimmel Cancer Center at Jefferson have identifiedcancer cell mitochondria as the unsuspecting powerhouse and "Achilles' heel" of tumor growth, opening up the door for new therapeutic targets in breast cancerand other tumor types.

"We and others have now shown that cancer is a 'parasitic disease' that steals energy from the host -- your body," Dr. Lisanti said, "but this is the first time we've shown in human breast tissue that cancer cell mitochondria are calling the shots and could ultimately be manipulated in our favor."

Mitochondria are the energy-producing power-plants in normal cells. However, cancer cells have amplified this energy-producing mechanism, with at least five times as much energy-producing capacity, compared with normal cells. Simply put, mitochondria are the powerhouse of cancer cells and they fuel tumor growth and metastasis.

The research presented in the study further supports the idea that blocking this activity with a mitochondrial inhibitor -- for instance, an off-patent generic drug used to treat diabetes known as Metformin -- can reverse tumor growth and chemotherapy resistance. This new concept could radically change how we treat cancer patients, and stimulate new metabolic strategies for cancer prevention and therapy.

Investigating the Powerhouse

Whether cancer cells have functional mitochondria has been a hotly debated topic for the past 85 years. It was argued that cancer cells don't use mitochondria, but instead use glycolysis exclusively; this is known as the Warburg Effect. But researchers at the Jefferson's KCC have shown that this inefficient method of producing energy actually takes place in the surrounding host stromal cells, rather then in epithelial cancer cells. This process then provides abundant mitochondrial fuel for cancer cells. They've coined this the "Reverse Warburg Effect," the opposite or reverse of the existing paradigm.

To study mitochondria's role directly, the researchers, including co-author and collaborator Federica Sotgia, Assistant Professor in the Department of Cancer Biology, looked at mitochondrial function using COX activity staining in human breast cancer samples. Previously, this simple stain was only applied to muscle tissue, a mitochondrial-rich tissue.

Researchers found that human breast cancer epithelial cells showed amplified levels of mitochondrial activity. In contrast, adjacent stromal tissues showed little or no mitochondrial oxidative capacity, consistent with the new paradigm. These findings were further validated using a computer-based informatics approach with gene profiles from over 2,000 human breast cancer samples.

It is now clear that cancer cell mitochondria play a key role in "parasitic" energy transfer between normal fibroblasts and cancer cells, fueling tumor growth and metastasis.

"We have presented new evidence that cancer cell mitochondria are at the heart of tumor cell growth and metastasis," Dr. Lisanti said. "Metabolically, the drug Metformin prevents cancer cells from using their mitochondria, induces glycolysis and lactate production, and shifts cancer cells toward the conventional 'Warburg Effect'. This effectively starves the cancer cells to death".

Personalized Treatment

Although COX mitochondrial activity staining had never been applied to cancer tissues, it could now be used routinely to distinguish cancer cells from normal cells, and to establish negative margins during cancer surgery. And this is a very cost-effective test, since it has been used routinely for muscle-tissue for over 50 years, but not for cancer diagnosis.

What's more, it appears that upregulation of mitochondrial activity is a common feature of human breast cancer cells, and is associated with both estrogen receptor positive (ER+) and negative (ER-) disease. Outcome analysis indicated that this mitochondrial gene signature is also associated with an increased risk of tumor cell metastasis, particularly in ER-negative (ER-) patients.

"Mitochondria are the 'Achilles' heel' of tumor cells," Dr. Lisanti said. "And we believe that targeting mitochondrial metabolism has broad implications for both cancer diagnostics and therapeutics, and could be exploited in the pursuit of personalized cancer medicine."

On Dec. 7, an early-morning press briefing has been scheduled for investigators to outline findings of four noteworthy studies.

- Swedish researchers will report that diabetes and obesity after age 60 are risk factors for breast cancer. Low lipids also increased risk, but high lipids did not in their study comparing medical records of more than 23,000 women. Similarly, risk went up with use of the diabetes drug glargine but down with metformin.

Does this mean that we should not be taking so much Lipitor and/or did they say what your lipids range should be? Our PCP is very aggressive in keeping our lipids low with statin drugs. Susan has been taking Simvastatin for years. I don't recall what her levels are, but they are always well below the levels that are considered problematic.

Susan's surgery cancerversary was yesterday, 12/9 (one year - hooray!), and she has been in the Metformin trial for about six months now. We go back to Vanderbilt next Wednesday for follow-up, labs, mammogram, etc., so I'll try to remember to ask about this.

I spent the day at the Vanderbilt Breast Center yesterday and I am now, as of today, participating in the trial. It was a pleasure to meet with Dr. Ingrid Mayer and the staff at Vanderbilt. I was impressed with the level and quality of care I received and they all treated me like I was royalty. No kidding.

Two tips I picked up about anyone taking metformin:

It is recommended to eat something every four hours. Do not skip any meals.

I was advised that metformin should be stopped about three days before and after receiving IV contrast that is used in CT scans. This is important to help avoid lactoacidosis. I need to do more research myself on lactoacidosis, but I understand it can be life-threatening, so halting metformin for a few days before and after receiving IV contrast definitely needs to be on our radar screens.

Hey, you had a pCR, K! Why are you entering a trial? Your chance of recurrence is almost nil. Metformin is not completely benign as a drug, from what I hear, and there isn't much evidence in favor of taking it if you aren't extremely overweight and/or diabetic. Why take it if your chance of recurrence is so low?

I, for one, am not willing to give this thing a second chance at me. I definitely fall in the camp of throw the book at it. I was stage 1, no nodes, RCB of 1 after neodjuvant Gemzar/Carboplatin and still did 4X TC adjuvant. My oncologist and the endocrinologist at Stanford felt that this drug had little downside and some possible, while not proven, benefit that they were willing to prescribe off label. I came to her with alot of ideas and research and this is the only one she felt had enough potential vs. risk that she thought if worth doing. There does seem to be alot of interest in the research community about metformin. Just look how much has been posted here since I started this post last summer.

The exact quote from my oncologist was "it isn't going to hurt you, and it might possibly be beneficial". Who knows if it will turn out to have been a good thing or not. It does make me feel like I am doing something to fight back.

I have been on the drug since late August. Have had a couple of blood panels to monitor and my glucose is in the same range as before taking. No liver or kidney changes. I am normal weight with no signs or family history of diabetes. I have diarrhea sometimes. I have some of the symtoms that others have mentioned - sweats, palpitations. Who knows if related, but I bet the surgical menopause and general survivor anxiety could account for all of the above!

I wouldn't do this without being under doctor care and supervision. I do echo the warnings of go off before a CT scan. I almost had to reschedule one, but they pulled labs to check liver function, which was fine. I generally hold off while fasting.

dmwolf - you always post such good info and research. What specifically makes you so hesitant about metformin? What do you know that we should all consider?

for those taking metformin, how much are you taking...I have heard many different things...500mg 3 x per day? is that just for diabetics or non diabetics as well...I have stage 4 tnbc, ned but want plan b thanks christi

Hi ChristiI am taking the same dose as Martin's wife Susan - 850mg 2x/day as part of the clinical trial(or placebo - hopefully not!!!).I understand that diabetics are excluded from the trial- the main rational for the trial is that there was evidence in Phase I and II trials that many diabetic women on Metformin with BC (and also under active BC treatment) were experiencing higher survivability/lower recurrence rates compared to non-diabetic women.

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